A novel series of 4-(4-Methoxyphenyl)-2-(methylthio)pyrimidine-5-carbonitrile was developed linked to an aromatic moiety -containing bridge and then evaluated for their cytotoxic activity against MCF-7 and K562 cell lines. Seven compounds exhibited the highest activity against both cell lines where compounds and were the most active against K562 cell line. Exploring their molecular mechanisms by enzyme inhibition assay on PI3Kδ/γ and AKT-1 showed that compound was promising more than with IC = 6.99 ± 0.36, 4.01 ± 0.55, and 3.36 ± 0.17 uM, respectively. Also, flowcytometric analysis revealed that caused cell cycle arrest at S-phase followed by caspase 3 dependent apoptosis induction. Mechanistically, compound proved to modulate the expression of PI3K, p-PI3K, AKT, p-AKT, Cyclin D1, and NFΚβ. Furthermore, toxicity study indicated good safety profile for . These findings suggest that the trimethoxy derivative has strong potential as a multi-acting inhibitor on PI3K/AKT axis targeting breast cancer and leukaemia.
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| http://dx.doi.org/10.1080/14756366.2022.2051022 | DOI Listing |
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